This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The goal of this project is to elucidate the molecular logic of normal and pathophysiologic Notch signaling. Notch proteins constitute the receptors for a fundamental signaling pathway that instructs cell fate decisions during development helps to maintain tissue homeostasis in the mature organism. Signals are communicated between adjacent cells via cell-cell contact, because both the receptors and the ligands are transmembrane proteins. Ligand binding activates Notch signaling by initiated a proteolytic cascade that ultimately releases the intracellular part of the Notch receptor from the membrane, allowing it to enter the nucleus and act as an accessory transcription factor. Major points of emphasis in our research are to elucidate the mechanism of Notch autoinhibiton prior to ligand engagement, the structural basis for recognition of Notch receptors by their ligands, and the structural basis for assembly of nuclear Notch transcription complexes.